Dystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Abnormal dopamine (DA) neurotransmission is consistently observed across many different forms of dystonia, but the DA defects that give rise to dystonia are poorly understood. L-DOPA-responsive dystonia (DRD) is considered a prototype disorder for understanding how abnormal DA neurotransmission evokes dystonia. DRD is characterized by childhood onset dystonia with diurnal fluctuation whereby symptoms worsen throughout the course of the day. The distinguishing feature of DRD is the dramatic improvement in symptoms after restoration of DA signaling with L-DOPA or DA agonists. Indeed, DRD is caused by mutations in genes critical for DA synthesis, including tyrosine hydroxylase (TH). DRD-causing TH mutations are associated with some residual TH activity whereas mutations that abolish TH activity cause childhood parkinsonism suggesting that TH activity and [DA] are critical determinants in the development of dystonia. However, the nature of the DA signaling dysfunction that gives rise to dystonia is unknown. To address this gap in our knowledge, we generated a knockin mouse bearing the human DRD-causing Q381K mutation in TH (DRD mice). Like the human disorder, DRD mice display reduced TH activity, a reduction in [DA], dystonic movements that worsen throughout the course of the active period and improvement in the dystonia in response to L-DOPA. Thus, DRD mice exhibit the core neurochemical and symptomatic features of human DRD, thereby providing us with the unprecedented opportunity to dissect the mechanisms underlying DRD from gene to behavior. Our preliminary data demonstrate that the dystonia is mediated by [DA] that is <1% of normal. A similar reduction in presynaptic DA in adults would cause parkinsonism. Therefore, divergent postsynaptic responses likely account for the differences in the neurological consequences of reduced DA transmission between Parkinson's disease (PD) and dystonia. Indeed, our preliminary data demonstrate D1R supersensitivity, hyperexcitability of medium spiny neurons (MSNs), a reduction in MSN dendrite number and abnormal corticostriatal innervation. Therefore, we will test the hypothesis that early life DA deficiency in combination with (mal)adaptive postsynaptic responses gives rise to dystonia by using a multidisciplinary approach to examine the pre- and postsynaptic consequences of reduced DA transmission associated with dystonia. The Specific Aims are: 1. To elucidate the relationship between monoamine metabolism and the severity of dystonia. 2. To determine the DA receptor subtype(s) and signaling defects that contribute to the dystonia. 3. To delineate alterations in th intrinsic and synaptic properties of D1 and D2R-expressing MSNs. 4. To examine the dendritic morphology and ultrastructural changes in corticostriatal synapses onto D1R and D2R-expressing MSNs in response to early-life DA deprivation in DRD mice.